Endoscopic therapy strategy for upper gastrointestinal early cancer complicated with esophagogastric varices

doi:10.21203/rs.3.rs-1550678/v1

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Research Article

Endoscopic therapy strategy for upper gastrointestinal early cancer complicated with esophagogastric varices

https://doi.org/10.21203/rs.3.rs-1550678/v1

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Background: Endoscopic ligation and histoacryl injection have become the main methods for esophagogastric varices (EGV) in cirrhosis patients. And endoscopic submucosal dissection (ESD) has been widely used in the treatment of early gastrointestinal cancer. The present study aims to discuss the endoscopic therapy strategy for upper gastrointestinal early cancer in cirrhotic patients companied with EGV.

Methods: This study retrospectively analyzed the clinical data and endoscopic treatment characteristics of 12 patients with cirrhosis complicated with both EGV and early tumor of the upper digestive tract.

Results: The therapeutic decision depends on the relative location of early cancer to EGV and the general condition of patients. The international normalized ratio (INR) should be corrected to be no more than 1.5 and the platelet count no less than 50×10⁶/ml. The early cancers were dissected if the lesions were far from the EGV. On the other hand, the EGV should be treated first if the early cancers were close to the varices. En bloc resection was 100% (11/11) for all ESD procedures. The average operation time was 55 min (25-180 min). No significant complications were observed during the perioperative period. During an average follow-up time of 22.2 months (16-28 months), neither local recurrence nor enlarged lymph nodes was found. The remaining one patient lost the ESD chance due to the cancer progression after transjugular intrahepatic portosystemic shunt (TIPS) treatment.

Conclusions: ESD is a safe and effective way to remove early gastrointestinal cancer in patients complicated with EGV after comprehensive evaluation.

Therapy strategy

Upper gastrointestinal early cancer

Esophagogastric varices

Endoscopic treatment is at present the first-line choice for esophagogastric varices (EGV) in cirrhosis patients, no matter for primary prevention or active bleeding [1]. Endoscopic submucosal dissection (ESD) had become a safe and effective treatment method for early upper digestive tract cancer, which had the advantages of less trauma, high complete resection rate, accurate pathological diagnosis and staging, and fast postoperative recovery [2, 3]. The main complications of ESD were bleeding and perforation [4]. When esophageal and gastric varices were associated with early upper gastrointestinal neoplasms, the complications of ESD therapy should theoretically be higher, especially bleeding.

Since Inoue [5] reported a case of endoscopic resection of carcinoma accompanied by esophageal varices in 1991, a series of cases had been reported. When varicose veins were above the lesion, endoscopic mucosal resection could be performed after endoscopic injection sclerotherapy (EIS) [6]. It had also been report that the lesion on the varicose vein was ligated together by endoscopic variceal ligation (EVL) [7]. Radiofrequency ablation could be used to directly eradicate the lesion when early esophageal cancer complicated with small diameter esophageal varices. When complicated with large diameter esophageal varices, early esophageal cancer could be treated with radiofrequency after EVL, which was also safe and effective [8]. However, the number of cases reported above was small and a complete treatment strategy had not been proposed.

In this pilot study we aimed to propose a complete treatment strategy based on our previous experience for this kind of patient. The therapeutic decision should be made according to whether the patient's coagulation function could tolerate surgery, the risk of near-term spontaneous rupture of varicose veins, the risk of rupture during ESD, and the relationship between mucosal lesions and varicose veins. Totally 12 patients have been enrolled in this study. En bloc resection was 100% (11/11) for all ESD procedures. No significant complications were observed during the perioperative period. During an average follow-up time of 22.2 months (16–28 months), no local recurrence was found on gastroscopy, and no enlarged lymph nodes were found on enhanced CT. We had formed a standard work flow for early cancer of the upper digestive tract companied with EGV (Fig. 5), which might simplify the medical decision.

Patient selection

From April 2019 to August 2020, 12 patients were diagnosed with both early gastrointestinal cancer and EGV due to cirrhosis at our institution. The early cancer lesions are located at or distant from the varices. Inclusion criteria: (1) cirrhosis with EGV diagnosed by medical history and abdominal CT examination; (2) the presence of EGV with early cancer of the upper digestive tract was confirmed by gastroscopy; (3) the early cancer lesions of the upper digestive tract were diagnosed as high-grade intraepithelial neoplasia or intramucosal carcinoma by Magnification Endoscopy (ME) with Narrow Band Imaging (NBI) and pathological biopsy, and no evidence of lymph node metastasis was indicated by enhanced CT; (4) INR ≤ 1.5 or platelet count ≥ 50×10⁶/ml; (5) Informed consent is signed. Exclusion criteria: (1) INR > 1.5 and platelet count < 50×10⁶/ml; (2) Without informed consent. Finally, we retrospectively identified 12 consecutive patients, who received following endoscopic treatment. Endoscopic grading of EGV was based on the LDRf classification defined by Ling Hu EQ which could clearly indicate the relationship between the lesion and the position of the varicose vein to help with selection and timing of treatment [9]. “L” represented the location of the varicose vein. The esophageal varices were divided into superior (s), middle (m) and inferior (i), and recorded as Les, Lem and Lei. Lg represented the gastric varices which were divided into founder (f), body (b) and antrum (a), and recorded as Lgf, Lgb and Lga, respectively. “D” represented the maximum diameter of the varices. “Rf” represented the risk factor for variceal bleeding.

Endoscopic Treatment Of Egv

The procedure was performed under intravenous anesthesia by two experienced endoscopic experts who had > 10 years of experience. For varices with esophageal mucosal lesions, esophageal varices were treated by endoscopic variceal ligation (EVL) or endoscopic injection sclerotherapy (EIS), and gastric varices by histoacryl injection (HI). The endoscopy was reexamined after 4 weeks. If there were residual esophageal varices, the ligation treatment was continued.

Endoscopic Submucosal Dissection Procedure

After general anesthesia, NBI-ME was used to define the extent of lesion. The marker was made 5mm away from the edge of lesion by Dual knife (Olympus, Japan). Mucosal incision about 5mm away from the marker was performed after sufficient submucosal injection with saline solution, and the following submucosal dissection was performed by traction with a clip and line. After the dissection of the lesion, the blood vessels exposed on the wound were coagulated by Coagrasper (FD-410LR, Olympus, Japan) to prevent delayed bleeding. Finally, the lesion was recovered and fixed for further pathology examination. The patients were fasted for 2 days after operation, supplemented with fluid and acid suppression, and resumed liquid diet on the 3rd day without complications.

Subsequent Treatment And Follow-up Plan

If postoperative pathology of the lesion extends beyond the mucosal layer, the patient received subsequent radiation therapy. Follow-up with endoscopy and enhanced CT was carried out at 6, and 12 months after the operation and every year thereafter.

Clinical and endoscopic characteristics of the patients

The clinical and endoscopic characteristics of the 12 upper gastrointestinal early cancer patients with EGV were shown in Table 1. All the patients were male, their average age was 58.9 years (range, 49-75 years). All patients had hepatitis B-related cirrhosis. Eleven patients were class B according to the Child-Pugh score, and the remaining one was class C. Eleven patients had early esophageal cancer, and the remaining one had early gastric cancer. The INR of all the patients was less than 1.5, and platelet count of three patients was between 30×10⁹/L and 50×10⁹/L. The location of lesions was presented in Table 1. Early esophageal cancer of 10 patients located overlying or beside the esophageal varices. The mean length of early esophageal cancer was 2.7 cm (range, 1-7 cm). The circumferential width ranged from 1/6 to 2/3.

Clinical outcomes and adverse events

A total of 9 patients took measures to alleviate the varices before ESD as the lesion was located overlying or close to the esophageal varices (Table 2). Different treatment measures were took according to specific circumstances. There was no significant alleviation in esophageal varices in 3 (case 3, 7 and 8) of the 9 patients at the time of ESD (Fig. 1). The esophageal varices and lesion of the case 9 were ligated together by EVL (Fig. 2). A representative patient (cases 6) with lesion on the varicose vein alleviated by EVL and EIS before ESD was shown in Fig. 3. Two cases (case 11 and 12) underwent ESD directly without any additional treatment, as the lesions were not close to the EGV with low bleeding risk. All ESD procedures were successful, and all lesions were completely dissected. As for the remaining case 10 whose esophageal varices were significantly relieved by TIPS, the cancerous lesion progressed distinctly beyond the indications for ESD after 4 months. Chemoradiotherapy were arranged for him finally (Fig. 4).

Large amount of intraoperative bleeding was avoided for all ESD procedure. The average operation time was 55 min (range, 25-180 min). No significant complications were observed during the perioperative period. The second day after operation, 2 patients (cases 2 and 11) received oral prednisolone therapy at a starting dose of 30 mg. No postoperative stricture were observed in any patient at 6 months after ESD. However, postoperative pathology of 2 cases (cases 4 and 11) reached to SM2. These two patients received additional standard radiotherapy. During an average follow-up time of 22.2 months (range, 16-28 months), no local recurrence was found on gastroscopy, and no enlarged lymph nodes were found on enhanced CT.

Bleeding of EGV caused by portal hypertension is a fatal complication of decompensated liver cirrhosis. Patients with cirrhosis may also have thrombocytopenia, prolonged clotting time and other problems. Therefore, cirrhosis is considered to be an important cause of complications during surgery. However, few studies revealed that endoscopic therapy is equally tolerable and effective in patients with cirrhosis compared with those without cirrhosis in most cases [10, 11, 12]. The primary and secondary prevention of EGV and the treatment of acute variceal hemorrhage can be carried out under endoscopy. ESD has been widely used in the treatment of precancerous lesions and early gastrointestinal cancer, with the advantages of less trauma, high complete resection rate, accurate pathological diagnosis and staging, and quick postoperative recovery [2, 3]. However, it should also be noted that endoscopic surgery for patients with cirrhosis is prone to bleeding, even leading to life-threatening massive bleeding [11]. The major complications of ESD are hemorrhage and perforation, and patients with cirrhosis of EGV complicated by superficial mucosal lesions of the upper digestive tract have a higher risk of complications of hemorrhage and perforation when receiving ESD treatment than patients without cirrhosis [13]. Therefore, the timing of treatment and the selection of treatment methods for such patients are much more complex than those for EGV or early gastrointestinal cancer alone.

Previous literature has reported that EMR or ESD was used to treat the early esophageal cancer in patients with esophageal varicose veins in cirrhosis successfully [5, 6, 7, 14]. Other reports have confirmed the safety and effectiveness of ESD for patients with cirrhosis complicated with Barrett’s-associated adenocarcinoma and early gastric cancer [15, 16, 17, 18, 19]. This study reviewed 12 cases of endoscopic therapy strategy of upper gastrointestinal early cancer with EGV in our single center. No serious complications, such as hemorrhage and perforation, occurred during and after ESD treatment in all patients. Compared to the previous reports involving only a few patients, the 12 cases we reported was the largest number so far.

For the specific treatment strategy of patients with cirrhosis of EGV complicated with superficial mucosal lesions of upper digestive tract, we mainly consider the following three aspects: first, whether the coagulation function can be resistant to surgery; second, the timing of treatment of varicose veins and mucosal lesions; third, the location relationship between mucosal lesions and varicose veins.

Complication such as prolonged clotting time and thrombocytopenia due to decompensated liver function in cirrhosis and hypersplenism are important constraints for patients to be able to endure invasive examination and treatment. It is reported that INR < 1.5 and platelet count of > 50×10⁹/L as the threshold for patients with cirrhosis to tolerate invasive surgical procedures safely [13, 20]. However, Repici et al. suggested that patients with INR > 1.33 and/or platelet count < 105×10⁹/L may have an increased risk of bleeding after ESD [21]. Therefore, for patients with poor coagulation function, the infusion of component plasma and platelet products before endoscopic treatment can be considered. In this study, 3 of the 12 patients had platelet count < 50×10⁹/L, but INR of all the patients was less than 1.5. During submucosal dissection, the dissection depth should be below the vascular plexus with prophylactic treatment of submucosal vessels during the procedure (Fig. 1). Therefore, no postoperative complications such as bleeding occurred.

The timing of endoscopic treatment for EGV and upper gastrointestinal early cancer is the key to reduce the complications of these two treatments. We believe that the best time and method of treatment should be selected after fully considering such factors as the risk of spontaneous rupture of varices in the near future, the risk of intraoperative rupture of ESD and the risk of progression for selective operation of mucosal lesions. While minimizing the risk of varicose vein bleeding, it is important to consider that the selective management of mucosal lesions does not affect the patient's prognosis. In this study, 9 of the 12 patients firstly received endoscopic treatment for EGV, and then further treated with ESD for mucosal lesions. After the end of the treatment of EGV, when the patient's general condition can tolerate surgery, ESD and other treatments should be performed for the mucosal lesions as soon as possible. Unfortunately, four months after TIPS, esophageal lesions of case 10 progressed significantly and the timing for ESD was missed.

The location of mucosal lesions in relation to varicose veins is also important in the choice of treatment. For esophageal varices accompanied by esophageal mucosal lesions, we used EVL therapy in the management of esophageal varices, and EIS was also used in one case (Case 6). However, EIS is usually not used in the management of esophageal varices before ESD, especially when the lesion is located on the varices, because it may lead to submucosal fibrosis or even scar formation, which increases the difficulty of complete resection of the lesion [22, 23]. In case 6, submucosal fibrosis was observed intraoperatively, and ESD was successfully completed with the help of traction by clip with dental floss (Fig. 3). Traction needs to control the force. If the traction force is too high, the muscularis propria will be pulled easily and lead to muscularis injury or even perforation.

Our study shows that ESD is a safe and effective way to remove early gastrointestinal cancer in patients complicated with esophageal varices. We propose the following treatment strategies as showed in Fig. 5. In conclusion, for the endoscopic treatment of EGV with upper gastrointestinal superficial mucosal lesions in cirrhosis, the optimal treatment strategy should be comprehensively measured from the coagulation function of patients, the timing of treatment of varices and mucosal lesions, and the relative position relationship. Further studies are needed to confirm this finding with a larger number of patients and long-term follow-up of such patients.

EGV esophagogastric varices; ESD endoscopic submucosal dissection; TIPS transjugular intrahepatic portosystemic shunt; EVL endoscopic variceal ligation; EIS endoscopic injection sclerotherapy; HI histoacryl injection

Chao Deng has no conflict of interest relevant to this study. Suhua Wu has no conflict of interest relevant to this study. Feng Xu has no conflict of interest relevant to this study. Lin Lv has no conflict of interest relevant to this study. Juan Li has no conflict of interest relevant to this study. Zhiji Chen has no conflict of interest relevant to this study. Zhihang Zhou has no conflict of interest relevant to this study. Song He has no conflict of interest relevant to this study. Informed consent has been obtained from the patients for the publication of their information and imaging.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This project was approved by the medical ethics committee of the Second Affiliated Hospital of Chongqing Medical University (NO.2020-39). All informed consent were signed be every patient.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors declare that the research was conducted without any commercial or fnancial relationships that could be construed as a potential confict of interest. This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.

Funding

This study was funded by Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (13-002-011, 13-004-009), Chongqing Appropriate technology for health (06-123, 06-137), and National Science Foundation of China (81972285).

Acknowledgement

We would like to thank for the above fundings

Author contributions

Writing—original draft preparation, CD#, SW# and FX; writing—review and editing, JL and ZC; supervision, LL; revised version, CD#, ZZ and SH. All authors read and approved the fnal manuscript.

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Table 1. The clinical and endoscopic characteristics of patients

No.	Gender	Age	Child-Pugh	INR	Platelet count	Classification of varices	Location of lesion	Circumferential extension
1	Male	51	B	0.93	85	Lesmi D1.0 Rf0	30-32cm	1/3
2	Male	52	B	1.01	102	Lesmi D1.0 Rf0	28-32cm	1/2
3	Male	65	B	1.22	48	Lesmi D1.5 Rf1	18-20cm	1/3
4	Male	57	B	1.35	51	Lemi D1.0 Rf0	24-27cm	2/3
5	Male	58	B	1.21	69	Lesmi D1.0 Rf0	21-24cm	1/2
6	Male	55	B	1.26	52	Lemi D1.0 Rf0	30-37cm	2/3
7	Male	64	B	1.29	43	Lesmi gf D1.5 Rf1	25-28cm	1/3
8	Male	75	B	1.09	51	Lemi gf D1.0 Rf1	29-31cm	1/2
9	Male	49	B	1.25	39	Lemi gf D1.0 Rf1	36-37cm	1/6
10	Male	56	B	1.48	99	Lesmi D1.5 Rf1	33-35cm	1/2
11	Male	70	C	1.41	80	Lei D0.3 Rf0	24-25cm	1/5
12	Male	55	B	1.48	51	Lesmi gf D1.0 Rf0	incisura angularis	2.0*1.5cm

Table 2. Therapeutic methods and outcome of patients

No.	Relative location to EGV	Treatment Timing for EGV	Therapeutic method for EGV	Classification of EGV after treatment	Therapeutic for EEC/EGC	Intraoperative blood loss	Operation time	Pathological diagnosis
1	close	before	EVL	Lemi D0.3 Rf0	ESD	5ml	30min	M1
2	close	before	EVL	Lemi D0.3 Rf0	ESD	5ml	50min	M2
3	close	before	EVL	Lesmi D1.5 Rf1	ESD	2ml	25min	M2
4	close	before	EVL	Lemi D0.3 Rf0	ESD	50ml	73min	SM2
5	close	before	EVL	Lesmi D0.3 Rf0	ESD	5ml	47min	M2
6	close	before	EVL+EIS	Lemi D0.3 Rf0	ESD	10ml	180min	M2
7	close	before	EVL+HI	Lesmi D1.5 Rf1	ESD	5ml	45min	M3
8	close	before	EVL+HI	Lemi D1.0 Rf1	ESD	2ml	30min	M1
9	close	same time	EVL+HI	Lemi D0.3 Rf0	EVL	2ml	40min	--
10	close	before	TIPS	Lei D0.3 Rf0	--	--	--	--
11	distant	no	no	Lei D0.3 Rf0	ESD	0ml	35min	SM2
12	distant	no	no	Lesmi gf D1.0 Rf0	ESD	5ml	50min	M

No competing interests reported.

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You are reading this latest preprint version

Endoscopic therapy strategy for upper gastrointestinal early cancer complicated with esophagogastric varices

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Patient selection

Endoscopic Treatment Of Egv

Endoscopic Submucosal Dissection Procedure

Subsequent Treatment And Follow-up Plan

Results

Discussion

Abbreviations

Declarations

References

Tables

Competing Interests

Status:

Version 1